pathway is not available and nucleophilic addition occurs at
the kinetic site. Surprisingly, when 1 equivalent of a strong
base such as sodium amide or sodium hydride is used we
observe a preference for formation of the thermodynamic
enolate.
We wanted to determine if milling time played a large role in
the selectivity that we observe. When the reactions were carried
out for 15 min, 2 h and 4 h the overall yields were lower but the
ratio of products were unchanged.
In conclusion, we report the first analysis of enolate chemistry
under high speed ball milling conditions. We demonstrated that
although ball milling is theoretically an extremely high energy
process, ball milled reactions can be selective and can be driven
by kinetics. We are currently investigating the stereochemical
nature of the process to determine if chiral auxiliaries will add
stereoselectivity under these novel reaction conditions. We have
also studied other ketones such as acetophenone and pinacolone
(3,3-dimethyl-2-butanone) with p-bromobenzylbromide and ob-
served similar results to using cyclohexanone as the substrate.
In addition, we reacted 2-methylcyclohexanone with benzyl
chloride and benzyl bromide and observed the enolate product
similarly to what is observed when p-bromobenzylbromide is
used as the electrophile. We are currently undergoing a more
complete substrate scope to examine the fundamental rules of
the process. In addition to our more complete substrate scope we
are in the process of developing a greener procedure for product
isolation. Ball milling can be an excellent asset for the reduction
of solvent waste and the generation of more environmentally
benign reactions. However, in order to achieve these goals we
must first understand the nuances of this process.
4 C. Suryanarayana, Prog. Mater. Sci., 2001, 46, 1–184.
5 L. Takacs, Prog. Mater. Sci., 2002, 47, 355–414.
6 B. Rodriguez, A. Bruckmann, T. Rantanen and C. Bolm, Adv. Synth.
Catal., 2007, 349, 2213–2233.
7 V. V. Boldyrev, J. Mater. Sci., 2004, 39, 5117–5120.
8 G. Kaupp, CrystEngComm, 2003, 5, 117–133.
9 G. Kaupp, CrystEngComm, 2006, 8, 794–804.
10 M. A. Mikhailenko, T. P. Shakhtshneider and V. V. Boldyrev,
J. Mater. Sci., 2004, 39, 5435–5439.
11 H. Zoz, D. Ernst, T. Mizutani and H. Okouchi, Adv. Powder Metall.
Part. Mater., 1997, (part 11), 35–42.
12 H. Zoz, D. Ernst, R. Reichardt, T. Mizutani, M. Nishida and H.
Okouchi, Adv. Powder Metall. Part. Mater., 1998, (part 6), 69–79.
13 H. Zoz, D. Ernst, R. Reichardt, H. Ren, T. Mizutani, M. Nishida
and H. Okouchi, Mater. Manuf. Processes, 1999, 14, 861–874.
14 A. Bose, K. Ameyama, S. D. Torre, D. J. Vigueras, D. Madan, T. S.
Wei, P. Hightower and H. Zoz, Adv. Powder Metall. Part. Mater.,
2002, 1/175–171/190.
15 G. Kaupp, J. Schmeyers, M. R. Naimi-Jamal, H. Zoz and H. Ren,
Chem. Eng. Sci., 2002, 57, 763–765.
16 H. Ren, H. Zoz, G. Kaupp and M. R. Naimi-Jamal, Adv. Powder
Metall. Part. Mater., 2003, 216–222.
17 P. Vogel, S. Figueira, S. Muthukrishnan and J. Mack, Tetrahedron
Lett., 2009, 50, 55–56.
18 D. C. Waddell and J. Mack, Green Chem., 2009, 11, 79–82.
19 J. Mack, D. Fulmer, S. Stofel and N. Santos, Green Chem., 2007, 9,
1041–1043.
20 J. Mack and M. Shumba, Green Chem., 2007, 9, 328–330.
21 E. Colacino, P. Nun, F. M. Colacino, J. Martinez and F. Lamaty,
Tetrahedron, 2008, 64, 5569–5576.
22 Y.-W. Dong, G.-W. Wang and L. Wang, Tetrahedron, 2008, 64, 10148–
10154.
23 N. Giri, C. Bowen, J. S. Vyle and S. L. James, Green Chem., 2008, 10,
627–628.
24 G. Mugunthan and K. P. R. Kartha, J. Carbohydr. Chem., 2008, 27,
294–299.
25 P. R. Patil and K. P. R. Kartha, J. Carbohydr. Chem., 2008, 27, 279–
293.
26 B. Icli, N. Christinat, J. Tonnemann, C. Schuttler, R. Scopelliti and
K. Severin, J. Am. Chem. Soc., 2009, 131, 3154–3155.
27 S. Li, W. Yan and W.-x. Zhang, Green Chem., 2009, 11, 1618–1626.
28 J. Mokhtari, M. R. Naimi-Jamal, H. Hamzeali, M. G. Dekamin and
G. Kaupp, ChemSusChem, 2009, 2, 248–254.
29 B. Rodriguez, A. Bruckmann and C. Bolm, Chem.–Eur. J., 2007, 13,
4710–4722.
30 We ball milled these reaction under an open atmosphere with no
decomposition of LiHMDS. Our, investigation on the ability to ball
mill hydroscopic reagents without precautions is a part of an account
which will be available soon.
Acknowledgements
We would like to thank the National Science Foundation (CHE-
0548150) for the financial support for this research. We would
also like to thank the National Science foundation, iREU, The
American Chemical Society and the Deutscher Akademischer
Austausch Dienst for the financial support for Indre Thiel to
conduct the research.
31 P. Anastas and J. Warner, Green Chemistry: Theory and Practice,
Oxford Publishing, Oxford, UK, 1998.
32 Y.-W. Dong, G.-W. Wang and L. Wang, Tetrahedron, 2008, 64, 10148–
10154.
Notes and references
33 M. Gall and H. O. House, Org. Synth., 1972, 52, 121–130.
34 H. O. House, L. J. Czuba, M. Gall and H. D. Olmstead, J. Org.
Chem., 1969, 34, 2324–2336.
35 I. Artaud, G. Torossian and P. Viout, Tetrahedron, 1985, 41, 5031–
5037.
1 K. Tanaka and F. Toda, Chem. Rev., 2000, 100, 1025–1074.
2 G. Rothenberg, A. P. Downie, C. L. Raston and J. L. Scott, J. Am.
Chem. Soc., 2001, 123, 8701–8708.
3 K. Tanaka and F. Toda, Solvent-Free Organic Synthesis, Wiley-VCH,
Weinheim, Germany, 2003.
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